Pancreatic cancer is resistant to conventional as well as novel anti-cancer therapies including TRAIL (Tumor Necrosis Factor-Related Apoptosis Inducing Ligand). Studies in our laboratories show that triptolide, a compound isolated from the Chinese plant Tripterygium wilfordii, sensitizes pancreatic cancer cells to cell death caused by TRAIL. These novel findings suggest that the combination of TRAIL and triptolide can emerge as an effective therapeutic strategy for pancreatic cancer. Our preliminary studies also provide some mechanistic insights and suggest that triptolide sensitizes pancreatic cancer cells to TRAIL induced cell death by two different mechanisms: 1) by sensitization of the lysosomes to TRAIL induced permeabilization; and 2) by abrogating TRAIL induced NF?B activation, thus counteracting pro-survival pathways induced by TRAIL. In Aim 1 of the current grant proposal, the efficacy of combination therapy will be evaluated in three unique but complementary animal models of pancreatic cancer. Aims 2 and 3 are designed to provide insights into the mechanism by which triptolide sensitizes pancreatic cancer cells to TRAIL induced cell death. In Aim 2 we will evaluate the novel hypothesis that triptolide downregulates Mcl-1, Bcl-2 and Bcl-xl (anti- apoptotic members of Bcl-2 family which sequester Bax/Bak). Release of Bax and Bak, which are then activated by TRAIL, allows them to translocate to lysosomes and induce lysosomal membrane permeabilization). In Aim 3 we will evaluate the novel hypothesis that triptolide downregulates TRIAL induced NF?B activation by inhibiting cIAP expression. Once unraveled, the mechanisms by which triptolide sensitizes pancreatic cancer cells to TRAIL will lead to the development of novel drug targets. Successful completion of these mechanistic and translational studies will eventually help in planning strategies to combine triptolide with TRAIL so that this combination can be used for the treatment of pancreatic cancer.